Cell Injury
Injury is defined as an alteration in cell structure or functioning resulting from some stress
that exceeds the ability of the cell to compensate through normal physiologic adaptive
mechanisms. Cells adapt to injurious stress by altering their structure or biochemical
processes to achieve a new “steady state” and maintain as normal as possible physiological
functions. If stressed cells cannot adequately adapt, critical cell function is impaired and the
cell is said to be injured. Injury may progress through a reversible stage, into
irreversible injury and culminate in cellular death. If cells are able to recover
their normal function after the stress is removed, the injury is said to be
reversible. Reversible injury includes reduced oxidation phosphorylation, ATP
depletion and cellular swelling. The damage becomes irreversible when the cell
reaches a “point of no return” and is destined for death. Irreversible damaged
cells can be identified by morphological and functional changes. Irreversibly
injured cells invariably undergo morphological changes that are recognised as
cell death of which there are two types; necrosis and apoptosis. When damage to
membranes is severe, lysosomal enzymes enter the cytoplasm and digest the
cell causing cellular contents to leak out, resulting in necrosis. Comparatively
apoptosis is a normal program of cell death that can be utilised to kill dead cells
by nuclear dissolution without complete loss of membrane integrity. There a
variety of causes of cell injury including hypoxia (oxygen deficiency), physical
injury (e.g. burns), chemical injury (poisons), infections (tuberculosis),
exaggerated immune reactions (e.g. autoimmue diseases) and genetic defects
(e.g. sickle cell anaemia).
The susceptibility of cells to injury is dependant on their cell type; labile, stable
and permanent cells. Labile cells have a relatively short lifespan and are
constantly replaced by continuously reproducing stem cells such as the
squamous epithelium of mucous membranes. Stable cells are generally in a
quiescent state and have a longer life span of months to years, but can be
stimulated to proliferate when necessary, e.g. regeneration of damaged/removed
liver cells. Permanent cells are not able to proliferate and are not able to
regenerate after injury such as cardiac and skeletal muscle cells and neurons.
Tissues composed of each cell type hence respond to injury differently. The
inherent vulnerability of particular types of cells to a given stress is also
important as some cells are more sensitive to stress than other cells. For
example, neurons are very susceptible to injury caused by hypoxia as they have
very little ability to use anaerobic respiration and can only survive 3-5 minutes
without oxygen. Cardiac muscle cells, hepatocytes and renal tubules can only
survive 30mins-2hrs without oxygen while skeletal muscle cells and fibroblasts
can last many hours before succumbing to injury due to hypoxia.
Mechanisms of injury
Cell injury is associated with damage to the structural and functional molecules of the cell.
Although any biologically important molecule in a cell can be the target of injury producing
stress, five systems are particularly vulnerable: the cell membrane, energy metabolism,
protein synthesis, cytoskeleton, and genetic apparatus. Because many of the biochemical
, systems of the cell are inter-dependent, injury at one site typically causes secondary injury to
other cellular processes.
ATP Depletion
Aerobic respiration and involving mitochondrial oxidative phosphorylation and
production of ATP is a key target of cell injury. Cells require a constant energy supply,
mainly in the form of ATP, to drive metabolism and biosynthetic reactions such as
membrane transport, protein synthesis, lipogenesis. The main ATP production in mammals
is oxidative phosphorylation that results in the reduction of oxygen by the electron transfer
system of mitochondria. Therefore depriving the cell of oxygen (hypoxia), or disturbing
mitochondrial function, interferes with the cell’s ability to utilize oxygen to generate adequate
amounts of ATP. This, in turn, impairs the ability of the cell to utilize nutrients to synthesize
structural and functional proteins necessary for maintaining the cell. ATP depletion causes
detachment of ribosomes from the ER which potentiates the reduction in protein synthesis.
This also reduces the activity of the plasma membrane ATP-dependent sodium pump
causes sodium and water accumulation in the cell resulting in cell swelling, dilation of the
endoplasmic reticulum, disruption of the cytoskeleton and cell contacts. Lack of oxygen and
the resultant depletion of ATP shifts energy metabolism towards anaerobic glycolysis which
generates ATP through metabolism until glycogen stores are depleted. In addition to being
less efficient in terms of energy production, glycolysis is also accompanied by the
accumulation of inorganic phosphate and lactic acid which lowers the intracellular pH. This
"acidosis" interferes with enzyme functioning and can damage nuclear DNA.
Influx of Intracellular calcium and loss of calcium homeostasis
-Calcium ions are important mediators of cell injury. Cytosolic calcium concentrations are
maintained at low levels compared with extracellular levels of calcium via membrane-
associated, energy dependent Ca/Mg-ATPase.
- Ischemia and certain toxins cause an early increase in cytosolic calcium concentration,
owing to the net influx of Ca across the plasma membrane and released from intracellular
calcium stores from mitochondria and endoplasmic reticulum.
-Sustained release in intracellular calcium ions subsequently results in non-specific increases
in membrane permeability. Increases calcium activates a number of enzymes such as
ATPases (thereby hastening ATP deletion), Phospholipases (which causes membrane
damage), proteases and endonucleases( breaks down DNA).
-Increased calcium also result in increased mitochondrial permeability and induction of
apoptosis. Hence increased in calcium mediates a variety of deleterious effects including cell
death.
Mitochondrial damage
Mitochondria are a major target of injury which is detrimental to the cell because
it is a source of energy for a cell. Cell injury is frequently accompanied by
Injury is defined as an alteration in cell structure or functioning resulting from some stress
that exceeds the ability of the cell to compensate through normal physiologic adaptive
mechanisms. Cells adapt to injurious stress by altering their structure or biochemical
processes to achieve a new “steady state” and maintain as normal as possible physiological
functions. If stressed cells cannot adequately adapt, critical cell function is impaired and the
cell is said to be injured. Injury may progress through a reversible stage, into
irreversible injury and culminate in cellular death. If cells are able to recover
their normal function after the stress is removed, the injury is said to be
reversible. Reversible injury includes reduced oxidation phosphorylation, ATP
depletion and cellular swelling. The damage becomes irreversible when the cell
reaches a “point of no return” and is destined for death. Irreversible damaged
cells can be identified by morphological and functional changes. Irreversibly
injured cells invariably undergo morphological changes that are recognised as
cell death of which there are two types; necrosis and apoptosis. When damage to
membranes is severe, lysosomal enzymes enter the cytoplasm and digest the
cell causing cellular contents to leak out, resulting in necrosis. Comparatively
apoptosis is a normal program of cell death that can be utilised to kill dead cells
by nuclear dissolution without complete loss of membrane integrity. There a
variety of causes of cell injury including hypoxia (oxygen deficiency), physical
injury (e.g. burns), chemical injury (poisons), infections (tuberculosis),
exaggerated immune reactions (e.g. autoimmue diseases) and genetic defects
(e.g. sickle cell anaemia).
The susceptibility of cells to injury is dependant on their cell type; labile, stable
and permanent cells. Labile cells have a relatively short lifespan and are
constantly replaced by continuously reproducing stem cells such as the
squamous epithelium of mucous membranes. Stable cells are generally in a
quiescent state and have a longer life span of months to years, but can be
stimulated to proliferate when necessary, e.g. regeneration of damaged/removed
liver cells. Permanent cells are not able to proliferate and are not able to
regenerate after injury such as cardiac and skeletal muscle cells and neurons.
Tissues composed of each cell type hence respond to injury differently. The
inherent vulnerability of particular types of cells to a given stress is also
important as some cells are more sensitive to stress than other cells. For
example, neurons are very susceptible to injury caused by hypoxia as they have
very little ability to use anaerobic respiration and can only survive 3-5 minutes
without oxygen. Cardiac muscle cells, hepatocytes and renal tubules can only
survive 30mins-2hrs without oxygen while skeletal muscle cells and fibroblasts
can last many hours before succumbing to injury due to hypoxia.
Mechanisms of injury
Cell injury is associated with damage to the structural and functional molecules of the cell.
Although any biologically important molecule in a cell can be the target of injury producing
stress, five systems are particularly vulnerable: the cell membrane, energy metabolism,
protein synthesis, cytoskeleton, and genetic apparatus. Because many of the biochemical
, systems of the cell are inter-dependent, injury at one site typically causes secondary injury to
other cellular processes.
ATP Depletion
Aerobic respiration and involving mitochondrial oxidative phosphorylation and
production of ATP is a key target of cell injury. Cells require a constant energy supply,
mainly in the form of ATP, to drive metabolism and biosynthetic reactions such as
membrane transport, protein synthesis, lipogenesis. The main ATP production in mammals
is oxidative phosphorylation that results in the reduction of oxygen by the electron transfer
system of mitochondria. Therefore depriving the cell of oxygen (hypoxia), or disturbing
mitochondrial function, interferes with the cell’s ability to utilize oxygen to generate adequate
amounts of ATP. This, in turn, impairs the ability of the cell to utilize nutrients to synthesize
structural and functional proteins necessary for maintaining the cell. ATP depletion causes
detachment of ribosomes from the ER which potentiates the reduction in protein synthesis.
This also reduces the activity of the plasma membrane ATP-dependent sodium pump
causes sodium and water accumulation in the cell resulting in cell swelling, dilation of the
endoplasmic reticulum, disruption of the cytoskeleton and cell contacts. Lack of oxygen and
the resultant depletion of ATP shifts energy metabolism towards anaerobic glycolysis which
generates ATP through metabolism until glycogen stores are depleted. In addition to being
less efficient in terms of energy production, glycolysis is also accompanied by the
accumulation of inorganic phosphate and lactic acid which lowers the intracellular pH. This
"acidosis" interferes with enzyme functioning and can damage nuclear DNA.
Influx of Intracellular calcium and loss of calcium homeostasis
-Calcium ions are important mediators of cell injury. Cytosolic calcium concentrations are
maintained at low levels compared with extracellular levels of calcium via membrane-
associated, energy dependent Ca/Mg-ATPase.
- Ischemia and certain toxins cause an early increase in cytosolic calcium concentration,
owing to the net influx of Ca across the plasma membrane and released from intracellular
calcium stores from mitochondria and endoplasmic reticulum.
-Sustained release in intracellular calcium ions subsequently results in non-specific increases
in membrane permeability. Increases calcium activates a number of enzymes such as
ATPases (thereby hastening ATP deletion), Phospholipases (which causes membrane
damage), proteases and endonucleases( breaks down DNA).
-Increased calcium also result in increased mitochondrial permeability and induction of
apoptosis. Hence increased in calcium mediates a variety of deleterious effects including cell
death.
Mitochondrial damage
Mitochondria are a major target of injury which is detrimental to the cell because
it is a source of energy for a cell. Cell injury is frequently accompanied by
